Pyridyl substituted thiazoles

ABSTRACT

Disclosed is a novel class of thiazole, thiadiazole, and oxadiazole compounds which are substituted at their nuclear carbons by aromatic moieties. These compounds exhibit antifungal activity against a variety of fungi including strains which have proven to be resistant to treatment with known antifungal agents such as Fluconazole.

1. This invention relates to a novel class of substituted azoles and,more specifically, diaryl substituted thiazoles, diaryl substitutedthiadiazoles and diaryl substituted oxadiazoles, compounds which areuseful in the treatment of fungal infections in mammals includinghumans. These compounds are active against a broad spectrum of fungisuch as Candida albicans, Candida parpsilosis, Candida tropicalis,Candida Krusei, Cryptococcus neoformans, Aspergillus fumigatus andTorulopsis glabrata. Moreover, compounds within this series are alsoactive against Fluconazole resistant strains and isolates.

BACKGROUND OF THE INVENTION

2. Opportunistic fungal infections are responsible for increasedmorbidity and mortality among patients suffering from AIDS and otherimmunocompromised diseases including infections resulting fromneutropenia, cancer chemotherapy and organ transplantation (Annals N.Y.Acad. Sc., 544:1-3).

3. Moreover, until recently, the treatment of deep seated fungalinfections has lagged behind the treatment of bacterial infections andonly a few systemic agents are available for combatting these invasivepathogens.

4. Current therapy provides for administering polyenes such asamphotericin B, allylamines such as Naftafin and Terbinafin and azolessuch as Fluconazole, Itraconazole and Ketoconazole. Amphotericin B, oncethe treatment of choice, is no longer favored due to the acute andchronic toxicities associated with its use.

5. Also, antifungal azoles are fungistatic, not fungicidal, and this hasresulted in azole resistant fungi, that is, fungi strains and isolateswhich are resistant to treatment with Fluconazole and other knownantifungal agents (New Engl. J. Med., 1944, 330: 263-272.)

KNOWN PRIOR ART

6. Azole compounds in which hydroxy and/or carboxy groups comprise themolecular structure are known to be useful in combatting pathogenicfungi.

7. For example, British Patent No. 2,099,818 and U.S. Pat. No. 4,404,216disclose Fluconazole

8. a triazole derivative which has played an important role inprotecting against a variety of fungi.

9. Also, DE-4124942 discloses azoles of the following structure havingantithrombotic and fibrinogen-binding activities:

Q¹ = A-B-C-N< Q² = A-B-C-CH< Q³ = A-B-C-C= Q⁴ = F-E-D-N< Q⁵ = F-E-D-CH<Q⁶ = F-E-D-C=

10. wherein: one of X¹-X⁵=Q¹-Q³, a second=Q⁴-Q⁶, a third=S, SO, N, R¹N,R²C, (R²)₂C, a fourth=O, S, N, SO₂, R²C, CO, and a fifth=R²C, (R²)₂C, N;A=cyano, (substituted) phenylene, pyridinylene, pyrazinylene,triazinylene, C=(substituted) phenylene, pyridinylene, pyrimidinylene,pyrazinylene, pyridazinylene, triazinylene, cycloalkylene)cycloalkylene, D=(substituted) alkylene, alkeylene, etc.; E=bond,alkylene, etc., F=carboxy, (substituted) alkoxycarbonyl; R¹=H, alkyl,aralkyl, aryl, heteroaryl; R=H, Cl, Br, alkyl, aralkyl, aryl,heteroaryl, alkoxy, R¹O₂C, (R¹)₂N, etc. These compounds are said to haveantithrombotic and fibrinogen-binding activity. The closest example is4-(4-amidinophenyl)-2-[4(2-carboxyethyl)phenyl]thiazole.

11. WO-9209586 (EP 0 513387 A1) discloses thiazole derivativesrepresented by the following structure useful as superoxide radicalinhibitors:

12. wherein:

13. R¹ is substituted phenyl, pyridyl, thienyl, carbostyril, pyrazyl,pyrrolyl, quinolyl, 3,4-dihydrocarbostyril;

14. R² is hydrogen, halo, alkyl, phenyl, alkoxycarbonyl, alkylamino, andthe like;

15. X is sulfur or oxygen;

16. R³ is Q (supra) wherein R is hydroxyl, carboxylic acid, alkyl,alkenyl and m is 0-2 or, R³ may be T (supra), wherein R⁴ is hydrogen oralkyl and R is aminoalkyl.

17. The structure activity relationship (SAR) of the above series hasbeen published in the J. Med. Chem. 1995, 38, 353-358 where thefollowing general structure is shown:

18. WO-9324472 (EP 0 600092 A1) discloses compounds of the followingstructure as an active oxygen inhibitor:

19. wherein:

20. R¹ is Ph which may be substituted by 1 to 3 alkoxy groups; and

21. R² is a substituted pyridylcarbonyl which may be substituted byalkoxycarbonyl, carboxyl, a 5 to 15 membered mono-, di-, or tricyclicheterocyclic ring residue having 1 to 3 N, O or S, atoms, or aphenylmoiety of the formula:

22. wherein, R³ represents carboxyl, lower alkoxycarbonyl, hydroxylsubstituted lower alkyl, lower alkoxy, tri-lower alkyl-substitutedsilyloxy, hydroxy, or hydrogen; R⁴ represents hydrogen, lower alkenyl orlower alkyl; R⁵ represents an amino-lower alkoxycarbonyl which may besubstituted further by lower alkyl, amino-lower alkoxy, or lower alkoxyor the like.

23. U.S. Pat. No. 4,791,200 describes compounds of the followingstructure useful as antisecretory agents:

24. wherein:

25. R is C1 to C4 alkyl, phenyl, phenyl substituted by CF₁, haloselected from I, Br or Cl, C1-C3 alkyl, alkoxy, acetamido, nitro, cyano,alkyamino or dialkylamino having 1-4 carbons or pyridyl.

26. R¹ is H or C1-C4 alkyl,

27. R² is H, C1-C4 alkyl, C1-C3 alkoxy or, Cl Br or I,

28. R³ or R⁴ are —O—(CH₂)_(m)—NR⁵R⁶ wherein m =1-3.

29. Patel and Colah in Bull Haff Instt. (1977), 5, 72-74 disclosep-(2-substituted-4-thiazolyl)phenylacetic acid andp-(2-substituted-4-thiazolyl)phenoxyacetic acids useful in treatingtuberculosis and fungi:

30. wherein R¹ is CH₂CCOOH or OCH₂COOH, and

31. Ar is phenyl, substituted phenyl or benzyl and the like.

32. Kirke et al in Bull, Haffkine Inst., (1977), 5, 75-7, and (1974), 2,28-31 disclose a series of thiazolyl-phenoxyacetic acids and derivativeshaving in vitro antituberculosis and antifungal activity against T.rubrum and T. mentagrophytes.

33. Anne et al in Antimicrob. Agents Chemother., (1980), 18(2), 231-9disclose diaryloxadiazole derivatives having only very weak activityagainst Candida albican (MIC₅₀>60 μg/ml) as, for example:

SUMMARY OF THE INVENTION

34. This invention relates to diaryl substituted azoles andpharmaceutically acceptable salts thereof useful as antifungal agents.

35. This invention also includes methods for preparing said azoles andantifungal compositions containing these compounds or a pharmaceuticallyacceptable salt thereof as the active ingredient.

36. The azoles of this invention are compounds of the general formula:

37. wherein:

38. Ar is phenyl, thienyl, pyridyl substituted with R¹R² where R¹, R²are independently hydrogen or halogen such as F, Cl, Br and I; alkyl,alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylthio, amino, hydroxyl,cyano, nitro, COOH, aminocarbonyl or aminosulfonyl, alkylamino,diakylamino, acylamino, dialkylaminosulfonyl, alkylaminosulfonyl,alkylamino, dialkylamino, acylamino, dialkylaminosulfonyl,alkylaminosulfonyl or, taken together, R¹, R² may form a ring—O—(CH₂)_(n)—O— wherein n=1,2.

39. R³, R⁴ are independently hydrogen, C1-C16 alkyl which may optionallybe substituted with amino, dialkylamino, hydroxy, cyano, carboxy;alkenyl, alkynyl, acyl or, taken together, R³ and R⁴ may be—(CH₂)m—Q—(CH₂)m′— where m′=m=2, Q=CH₂,O, S(O)_(n), n=0-2, NR⁷ whereinR⁷ is C1-C3 alkyl with the proviso that when Q is CH₂, m′ can also be 1.

40. R⁵ is H, halogen as defined above, OR, OH, NO₂, NH₂ or NHCOR where Ris lower alkyl, alkyl or aryl, and the like.

41. X is N, O or S;

42. Y is N or S, with the proviso when X=O or S, Y must be N;

43. Z is N or CR⁸, where R⁸ is hydrogen, halogen such as Cl, Br or I,lower alkyl or alkoxycarbonyl, with the proviso that X, Y and Z cannotall be N at the same time.

44. V is N, O or S, and when V is N, it may also be combined with R³ andR⁴ to form a heterocycle such as pyrrole, imidazol-1,2,4,-triazole,1,3,4-triazole and pyrazole, and when V is O or S, R³ and R⁴ combine toform a single substituent having the definition of R⁴ alone; and

45. P is an integer having a value of 1-3.

46. Specifically, this invention relates to thiazoles of the formula:

47. wherein: R¹, R², R³, R⁴, R⁵, p and V are each as defined above informula (I) and R⁶ is hydrogen, halogen, carboxy, alkoxy carbonyl, loweralkyl, hydroxy and lower alkoxy and the nontoxic pharmacologicallyacceptable salts thereof.

48. This invention also relates to thiadiazoles of the followingformula:

49. wherein: R¹, R², R³, R⁴ ₁ R⁵, p and v are each as defined above informula (I) , and the nontoxic pharmaceutically acceptable saltsthereof.

50. This invention also relates to thiadiazoles of the formula:

51. wherein: R¹, R², R³, R⁴, R⁵, p and V are as defined above in formula(I), and the nontoxic pharmaceutically acceptable salts thereof.

52. This invention also relates to oxadiazoles of the formula:

53. wherein: R¹, R² ₁ R³, R⁴, R⁵, p and V are as defined above informula (I), and the nontoxic pharmaceutically acceptable salts thereof.

54. More specifically, this invention relates to thiazoles of theformula:

55. wherein: R¹, R², R³, R⁴, are as defined above in formula (I), andthe nontoxic pharmaceutically acceptable salts thereof.

56. This invention also relate to diazoles of the formula:

57. wherein: R¹, R², R³, R⁴ are as defined above and X is O or S, andpharmaceutically acceptable salts thereof.

58. Alternatively and according to another embodiment, the preferredproducts of this invention are those represented by the formulaeidentified as VIII-XIIl hereinbelow.

59. In general, the preferred products are those which conform toformula VIII and formula IX:

60. wherein:

61. A₈ is selected from among pyridyl, halo substituted pyridyl and

62. where R⁸ is hydrogen, halo, nitro, amino, triflouromethoxy,pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl andtrimethylsilyl lower alkynyl; and R⁹ is hydrogen, nitro, lower alkoxy orcyano;

63. X is S or O;

64. Y is CH or N;

65. Z is CH or N;

66. B is lower alkylene or lower alkynylene;

67. D is SR¹⁰, OR¹¹ or N(R¹²R¹³) wherein R¹⁰ is di-loweralkylaminoalkyl; R¹¹ is di-lower alkylaminoalkyl, lower alkenyl, loweralkynyl or lower alkoxyakyl; R¹² and R¹³ are the same or different andrepresent hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl,lower alkoxyalkyl, lower cycloalkyl, lower dialkylaminoalkyl,hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower alkyl,di-lower alkylaminoalkylcarbonyl or, taken together, R¹² and R¹³ may becombined to form —CH₂CH₂N(R¹⁴)CH₂CH₂— or —CH₂CH₂SCH₂CH₂— where R¹⁴represents lower alkyl; and

68. R¹⁵ is hydrogen, nitro, amino, lower alkanamido or hydroxy; and thenontoxic pharmacologically acceptable salts thereof.

69. Another preferred embodiment are the thiazole compounds representedby formula X:

70. wherein:

71. R⁸ is hydrogen, halo, nitro, amino, triflourometnoxy, pyrrolyl,lower alkoxy, trifluoromethyl, cyano, lower alkynyl, trimethylsilyllower alkynyl; and R⁹ is hydrogen, nitro, lower alkoxy or cyano;

72. R¹² and R¹³ are the same or different and represent hydrogen, loweralkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lowercycloalkyl, lower dialkylaminoalkyl, hydroxy-lower alkyl, loweralkylaminoalkyl, mononuclear lower alkyl, di-loweralkylamincalkylcarbonyl or, taken together, R¹² and R¹³ may be combinedto form —CH₂CH₂N(R¹⁴)CH₂CH₂— or —CH₂CH₂SCH₂CH₂— wherein R¹⁴ representslower alkyl;

73. R¹⁵ is hydrogen, nitro, amino, lower alkanamido or hydroxy, and

74. n is an integer having a value of 1 to 3, and the nontoxicpharmacologically acceptable salts thereof.

75. Still another preferred embodiment are thiazoles of the followingformula:

76. wherein:

77. R¹⁶ is hydrogen, halo, nitro, lower alkoxy, cyano, trifluoromethylor lower alkyl;

78. R¹⁷ is hydrogen, nitro, halogen or cyano;

79. R¹⁸ and R¹⁹ are the same or different and represent hydrogen, loweralkyl, lower alkenyl, di-lower alkylaminoalkyl, hydroxy lower alkyl andlower alkylaminoalkyl; and

80. R²⁰ is hydrogen or hydroxy, and the nontoxic pharmacologicallyacceptable salts thereof.

81. Another preferred embodiment provides for diazoles having theformula:

82. wherein

83. R²¹ is selected from among hydrogen and lower alkoxy;

84. R²² is selected from among hydrogen and nitro; and

85. R²³ and R²⁴ are lower alkyl, and the nontoxic pharmacologicallyacceptable salts thereof.

86. Also included among the preferred embodiments are thiadiazoles offormula XIII:

87. wherein:

88. E is SR²⁶ or NR²⁷R²⁸ wherein R²⁶ is di-lower alkylaminoalkyl R²⁷ andR²⁸ are the same or different and represent lower alkyl and loweralkenyl, and the nontoxic pharmacologically acceptable salts thereof.

89. The aforecited compounds are useful in the treatment of broadspectrum fungal infections, and they are also active against a varietyof fungi and fungal isolates including Fluconazole-resistant isolatesand strains. These compounds are useful for this purpose when used inthe concentration range of 250 μg/ml and below.

90. Appropriate compounds of formula I to XIII are useful in the freebase form, in the form of base salts where possible, and in the form ofacid addition salts. In practice, use of the salt form is equivalent touse of the base form.

91. Pharmaceutically acceptable salts within the scope of this inventionare those derived from mineral acids such as hydrochloric acid andsulfuric acid and the like including organic acids such asethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, andthe like. These afford the corresponding hydrochloride, sulfate,ethanesulfonate, benzenesulfonate, p-hydrochloride and the like,respectively; however, this invention is not limited to those mentionedabove since equivalent salts will be apparent to those skilled in thisart.

92. Examples of pharmaceutically acceptable base addition salts includeorganic bases which are nontoxic and of such strength as to form usablesalts. These organic bases form a class whose limits are readilyunderstood by those skilled in the art, and for the purposes ofillustration, they include mono-, di, and trialkylamines such asmethylamine, dimethylamine, and triethylamine; mono-, di-, ortrihydroxyalkylamines such as mono-, di-, or triethanolamine, aminoacids such as arginine and lysine; quanidine; N-methyl-glucosamine;N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine;ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl)aminomethane; and the like. (See, for example, “Pharmaceutical Salts,”J. Pharm. Sci., 66(1) :1-19 (1977).) Salts of inorganic bases includesodium, potassium, calcium or the like.

93. The acid addition salts of said basic compounds are prepared eitherby dissolving the free base of compound I to XIII in aqueous or aqueousalcohol solution of other suitable solvents containing appropriate acidand isolating the salt by evaporating the solution, or by reacting thefree base of compound I to XIII, having an acid group thereon with abase such that the reactions are in an organic solvent, in which case,the salt separates directly or can be obtained by concentration of thesolution. Salts can also be prepared by adding base to an aqueousalcohol solution of another salt.

94. Generally, the compounds of formulas (I) to (XIII) can be preparedby the processes identified as 1-9 hereinbelow:

95. Process 1 (Scheme 1):

96. In this process (Scheme 1), the substituted thiobenzamide (2) isprepared according to the literature procedure (Tetrahedron, 41, (22) ,5061, 1985, M. Cava and M. Levinson) by refluxing benzamide (1) withLawesson's reagent in dry benzene or toluene (M. Levinson). Acondensation reaction between the thiobenzamide and α-haloacetophenonederivatives in solvent such as low alcohol, THF, CH₃CN, etc., gives2,4-diarylthiazole compounds (3) (Organic Synthesis, Coll. III, 332).The NBS bromination of the compound (3) affords the bromomethyl products(4a) and/or (4b) , which are converted to compounds (5) and (6)respectively by reacting with appropriate nucleophile as shown inScheme 1. Compound (5) can also be de-brominated by catalytichydrogenation to give compound (6).

97. Process 2 (Scheme 2):

98. An alternative synthetic pathway is illustrated in Scheme 2, whichinvolves the bromination of ethyl 4-acetylbenzoate with bromine in etherin the presence of catalytic amount of aluminum chloride, Theα-bromoacetophenone compound (7) is then condensed with appropriatethiobenzamide (2) as described before to form the diarylthiazolederivatives (8) Subsequent reduction of the ester with LAH followed bybromination with carbontetrabromide and triphenylphosphine yields thebromide (4a) which upon nucleophilic substitution produces the targetproduct (6). Compound (6) can also be prepared through the mesylatedintermediate (9), which is prepared by the reduction of compound (8)with LAH followed by mesylation with methanesulfonyl chloride.

99. A compound represented by the general formula (II) wherein p=2-3 canbe prepared by the process as shown in Scheme 3 and Scheme 4:

100. Process 3 (Scheme 3):

101. Compound (11) is obtained by condensation and cyclizationthiobenzamide (2) and a-bromoaceophenone (10), which is made by thebromination reaction as described before. By refluxing compound (11) inacetone with excess amount of Nal produces the iodoanalog (12) which onreaction with nucleophile produces product (13).

102. Process 4 (Scheme 4)

103. In order to prepare a compound represented by the general formula(II) wherein p=3, a palladium-catalyzed C—C coupling reaction betweenthe 4-(p-brornophenyl)thiazole derivatives (14) and an acetylenicreactant is employed. Catalytic hydrogenation of the coupling product(15) gives the extended three carbon side chain compounds (16) in verygood yield (Scheme 4).

104. Process 5 (Scheme 5)

105. Primary amine sidechain compounds (18) can be prepared from thebromo compounds (4a) by the use of methenamine followed by cleavage ofthe resulting quaternary amine salts with ethanolic HCl (OrganicSynthesis, Coll. V, 212). The secondary amine sidechain compounds (21)(Scheme 5) are prepared by acetylation of compounds (18) withtrifluoroacetic anhydride to give the amide analogs (19) quantitatively.Treatment of the compound (19) with NaH in anhydrous DMF followed byalkylation with alkyl halide affords compound (20), which can beconverted to the secondary amine products (21) by cleavage of thetrifluoroacetyl group in a basic media. Compound (21) is transformed totarget compounds (6) by treatment with base such as K₂CO₃ andappropriate alkyl halide.

106. Process 6 (Scheme 6)

107. The α-bromoacetophenones with the desired dialkylamino alkyl groups(23) are synthesized and coupled with substituted thiobenzamides (2) togive target compounds (Scheme 6). 4′-Methyl acetophenone or derivativesthereof are treated with NBS in CCl₄ under refluxing condition to givethe corresponding benzylbromides (22) which are subsequently treatedwith the requisite dialkylamines at room temperature to give thedialkylamino alkyl derivatives (23). These compounds are purified viaflash chromatography, converted to the corresponding HCl salt, andbrominated with Br₂ to give α-bromoacetophenones (24) Compounds (24) arereacted with substituted thiobenzamides (2) under refluxing EtOH orsimilar solvent to give the target compounds (25) as a mixture of HCland HBr salts. These are converted to the free base and purified viaflash chromatography as needed. Compounds wherein R⁷ is not hydrogen arefurther derivatized to additional targets. For example, compound (25)(R⁷=NH₂) which is eventually treated with Ac₂O to give the N-acetylaminocompound (27) (R⁷=NHCOCH₃)

108. Process 7 (Scheme 7)

109. Following the procedure described in process 1, the desiredthiobenzamnide (2) is reacted with 3′methoxy-α-bromoacetophenone inrefluxing EtOH to give the thiazole (28). This compound is demethylatedwith BBr₃ under standard condition to give the corresponding phenol(29). This is treated with a mixture of paraformaldehyde and requisitedialkylamine under refluxing EtOH to give target dialkylaminomethylcompounds (30).

110. Process 8 (Scheme 8)

111. A compound represented by the general formnula (III) can beprepared by the process as shown in Scheme 8:

112. On the basis of a known procedure (Adv. Heterocycl. Chem., 1982,32, 285), p-methylbenzimidate hydrochloride (31) is prepared by bubblinghydrogen chloride gas through a cooled solution of p-tolunitrile inmixed solvents (1:1=chloroform and methanol). Treatment of benzimidate(31) with ammonia/methanol solution gives amidine hydrochloride (32)with ammonia/methanol solution gives amidine hydrochloride (32)quantitatively. The amidine (32) is then reacted with one equivalent ofperchloromethylmercaptan in the presence of triethylamine at zero degreeto give a cyclized product, 5-chloro-1,2,4-thiadiazole (33) as yellowsolid. Coupling of 5-chloro-1,2,4-thiadiazole with substituted aryl.Grignard Reagents in dry THF provides the desired diaryl1,2,4-thiadiazoles (34) (J. Am. Chem. Soc., 1985, 107, 2033 andorganometallics, 1993, 12, 3468). Subsequent bromination followed bynucleophilic substitution as described in Preparation Process 1, affordsthe final product (36).

113. Process 9 (Scheme 9)

114. A compound represented by the general formula (IV) and (V) can beprepared by Ltie following process:

115. The N,N′-diacylhydrazine compound (J. Chem.Soc, (C), 1970, 1397)(37) is prepared by acylation of the substituted benzhydrazide at zerodegree with p-methylbenzoyl chloride. The N,N′-diacylhydrazine compound(37) is heated either with thionyl chloride to produce the cyclizedproduct, 1,3,4-oxadiazole (38a) or with Lawesson's Reagent* to exchangethe oxygen to give sulfur and then cyclize to 1,3,4-thiadiazoles (38b).

116. One of ordinary skill in the art will recognize variations in thesequence and variations in the appropriate reaction conditions from theanalogous reactions shown or otherwise known which may be appropriatelyused in the processes above to make the compounds of Formulae I to XIIIherein.

EXAMPLE 1

117.2-(4′-fluorophenyl)4-[4″-(N-methyl-N-allylaminomethyl)phenyl]thiazole(VI:R₁=H, R₂=4-F, R₃=Me, R₄=allyl, V=N (Process 1, Scheme 1)

118. 4-Fluorobenzamide (5.0 g, 35.9 mmol) in benzene (100 ml) is addedLawesson's reagent (7.27 g, 18.0 mmol) and the resulting solution isheated to reflux for 1 hour. The solution is cooled to room temperature,concentrated and water (150 ml) added. The mixture is heated to refluxfor 3 hours, and cooled to room temperature. The precipitate is filteredand dried under vacuum to yield 4-fluorothiobenzamide as a yellow solid(4.1 g, 71%).

119.¹H NMR (CDCl₃) δ7.09 (t, 2H), 7.90 (dd, 2H).

120. To a solution of the crude product of 4-fluorothiobenzamide (2.0 g,12.9 mmol) in EtOH (30ml) is added 2-bromo-4′methylacetophenone (2.75 g,12.9 mmol). The mixture is heated to reflux for 24 hours. The course ofthe reaction is followed by thin layer chromatography. Upon completionof the reaction the solution is cooled to room temperature and the whiteprecipitate filtered and dried under vacuum to yield2-(4′-fluorophenyl)-4-(p-tolyl) thiazole (1.54 g, 54%).

121.¹H NMR (DMSO_(d6)) : δ2.35 (s, 1H), 7,28 (d, 2H), 7.38 (t, 2H), 7.94(d, 2H), 8.08 (dd, 2H), 8.11 (s, 1H).

122. To a solution of 2-(4′-fluorophenyl)-4-(p-tolyl)-thiazole (1.49 g,5.5 mmol) in CCl₄ (50 ml) is added NBS (1.09 g, 6.1 mmol) and benzoylperoxide (50 mg) and the reaction mixture is heated to reflux. Anadditional 50 mg of benzoyl peroxide is added every hour for 4 hours.The mixture is refluxed for 24 hours and then filtered through celite.The mother liquor is concentrated to yield a yellow oil which istriturated with pentane and filtered to yield 2-(4′-fluorophenyl)-4-[p-(bromomethyl)phenyl)]thiazole (1.45 g, 75%).

123.¹H NMR (DMSO_(d6)) δ4.77 (s, 2H), 7.39 (t, 2H), 7.58 (d, 2H), 8.08(m, 2H), 8.22 (s, 1H).

124. To a solution of2-(4′-fluorophenyl)-4-(p-bromomethylphenyl)-thiazole (1.00 g, 2.87 mmol)in EtOH (20 ml) is added dropwise N-methyl allylamine (0.45 g, 6.00mmol) in EtOH (10 ml). The solution is stirred at room temperature for12 hours and the solvent is removed under reduced pressure to yield agreen oil. The oil is taken up in CH₂Cl₂ (30 ml) and washed with 1N NaOH(30 ml) and brine (30 ml). The organic layer is dried over anhydrousK₂CO₃ and concentrated. The residue is chromatographed on a silica gelcolumn eluting with MeOH:CHCl₃ (5:95) to yield a yellow oil. Theresulting oil is dissolved in MeOH (5ml) to which is added excessHCl/MeOH solution (1096 w/w, lml) and stirred for 1 hour. The solvent isremoved under reduced pressure, and the residue recrystallized fromisopropanol to yield the title compound as HCI salt as a brown solid(0.43 g, 40%).

125.¹H NMR (DMSO_(d6)) δ2.60 (d, 3H), 3.70 (m, 2H), 4.35 (m, 2H), 5.51(s, 1H), 5.59 (d, 1H), 6.08 (m, 1H), 7.40 (t, 2H), 7.72 (d, 2H), 8.12(m, 4H), 8.30 (s1, H).

EXAMPLE 1a

126.2-(4′-Chlorophenyl)-4-[[4′-(2-N,N-dimethylaminoethyl)thio]methyl]phenyl]thiazole(II:R¹=H²=4—Cl, V=S, R³, R⁴=CH₂CH₂NMe₂, R⁶=H)

127. Replacing 4-fluorobenzamide with 4-chlorobenzamide in the aboveexperiment the compound2-(4′-chlorophenyl)-4-[(p-bromomethyl)phenyl]thiazole is obtained.2-Dimethylaminoethanethiol hydrochloride (0.7 g, 5.0 mmol) is added to aslurry of NaH (60%, 0.44 g, 11 mmol) in THF (20ml) and the suspensionstirred for 1 h. A solution of the above bromomethyl compound (1.82 g,5.0 mmol) in THF (20 ml) is added with stirring and the reaction mixturestirred for 4 h. THF is distilled, the residue is poured into water andthe mixture is extracted with EtOAc. The EtOAc extract is washed withbrine, dried, stripped and the residue chromatographed (SiO₂, 100 g,CHCl₃ —CHCl₃/MeOH 5%) to give the title compound as a soft solid (0.75g), mp. 51-52° C.

128.¹H NMR (CDCl₃): 2.20 (s, 6 H), 2.40-2.60 (m, 4 H), 3.80 (s, 2 H)7.35-7.50 (m, 5 H), 7.85-8.00 (m, 4 H).

EXAMPLE 1b

129. 2-(4′-Chlorophenyl-4 -[[4-(N-methylpiperazinyl)methyl]phenyl]thiazole (II: R¹=H, R²=4-Cl, V=N,R³R⁴=(CH₂CH₂)₂NMe, R⁶=H)

130. To a suspension of2-(4′chlorophenyl)-4-[(p-bromomethyl)-phenyl]-thiazole (1.0 g, 2.74mmol) and anhydrous K₂CO₃ (0.83 g, 6 mmol) in DMF (15 ml) is added asolution of N-methyl piperazine (0.3 ml, 2.74 mmol) in DMF (1 ml) withstirring. The reaction mixture is stirred for 18 h at rt. It is pouredinto water (100 ml) and the organic material is extracted with EtOAc.The EtOAc layer is washed with brine, dried, stripped, and the residuechromatographed (SiC₂, 30 g, CHCl₃/CHCl₃/MeOH 5%) to give the titlecompound (0.43 g), mp. 110-111° C.

131.¹H NMR (CDCl₃) 2.25 (s, 6 H), 2.35-2.60 (br s, 8 H), 3.55 (s, 2 H),7.35-7.50 (m, 5 H), 7.90-8.05 (m, 4 H).

132. Additional examples are shown in Table I.

EXAMPLE 2

133.2-(4′-methoxyphenyl)-4-[4″-(N-allyl-N-methylamino-methyl)phenyl]thiazole(VI: R₁=H, R₂=4-MeO, R₃=Me, R₄=allyl) (Process 2, Scheme 2)

134. To a solution of ethyl 4-acetylbenzoate (5.12 g, 26.6 mmol) inether (50 ml) containing aluminium chloride (0.025 g, 0.19 mmol) isadded bromine (1.31 ml, 26.6 mmol) and the reaction mixture is stirredfor 2 h. The reaction mixture is poured into saturated NaHCO₃ solutionand stirred for 30 min. and the layers are separated. The organic layeris washed with NaHCO₃, H₂O, dried over MgSC₄, concentrated to half ofits volume and refrigerated overnight. The resulting solid is filteredto yield ethyl 4-(2′-bromoacetyl) benzoate (5.89 g, 81.6%) as whitecrystals.

135.¹H NMR (CDCl₃): δ1.42 (t, 3H), 4.42 (q, 2H), 4.48 (s, 3H), 8.04 (d,2H), 8.16 (d, 2H).

136. To a solution of 4-methoxythiobenzamide (1.50 g. 8.97 mmol) inethanol (50 ml) is added ethyl 4-(2′-bromoacetyl)-benzoate (2.43 g, 8.97mmol) and the reaction mixture is heated to reflux for 4 hours. Thereaction mixture is cooled to room temperature and the precipitate isfiltered to yield ethyl p-[2-(4′-methoxy)phenyl-thiazol-4-yl]benzoate(2.15 g, 70.1%) as a light yellow solid.

137.¹H NMR (CDCl₃): δ1.42 (t, 3H), 3.87 (s, 3H), 4.40 (q, 3H), 6.98 (d,2H), 7.53 (s, 1H), 7.96-8.14 (m, 6H).

138. To a slurry of LAH (167 mg, 4.41 mmol) in dry THF (10 ml) is addeddropwise a solution of ethylp-[2-(4¹-methoxyphenyl)-thiazol-4-yl]benzoate (500 mg, 1.47 mmol) in dryTHF (10 ml) and the reaction mixture is stirred at room temperature for18 hours. A solution of saturated (NH₄)₂SO₄ (20 ml) is added to thereaction mixture and stirred for 30 min. The precipitate is filtered,and the aqueous layer is washed thoroughly with ethyl acetate. Thecombined organic layer is washed with H₂O and brine, dried over MgSO₄and concentrated in vacuo to yield2-(4′-methoxyphenyl)-4-(4″-hydroxymethylphenyl)-thiazole (360 mg, 82.2%) as a white solid.

139.¹H NMMR (CDCl₃) δ3.89 (s, 3H), 4.76 (s, 2H), 6.98 (d, 2H), 7.42 (s,1H), 7.46 (d, 2H), 7.97-8.02 (m, 4H).

140. To a solution of2-(4′-methoxyphenyl)4-(4″-hydroxymethylphenyl)-thiazole (355 mg, 1.13mmol) in dry THF (10 ml) at 0° C. is added triphenylphosphine (446 mg,1.70 mmol) and carbon tetrabromide (564 mg, 1.70 mmol). The reactionmixture is stirred for 17.5 h at 0° C. The precipitate is filtered andthe filtercake is washed with THF. The filtrate is concentrated invacuum and purified by column chromatography eluting with 10% ethylacetate/hexane to yield2-(4′-methoxyphenyl)-4-(4″-bromomethylphenyl)-thiazole (285 mg, 70%) asa white solid.

141.¹H NMR (CDCl₃): δ3.88 (s, 3H), 4.56 (s, 2H), 6.98 (d, 2H), 7.43 (s,1H), 7.46 (d, 2H) 7.95-8.01 (m, 4H).

142. The above bromomethyl compound is aminated following the procedureas described in Example 1 giving the title compound2-(4′-methoxyphenyl)-4-[4″-(N-allyl-N-methylaminomethyl)phenyl]-thiazolein 95% yield.

143.¹H NMR (CDCl₃) δ2.51 (s,3H), 3.56-3.90 (m, 2H), 3.85 (s, 3H),4.19-4.46 (m, 2H), 5.51-5.60 (m, 2H), 5.98-6.29 (m, 1H), 7.11 (d, 2H),7.70 (d, 2H), 7.98 (d, 2H), 8.12 (d, 2H), 8.20 (s, 1H) , 11.12 (br s,1H).

EXAMPLE 2a

144. (Process 2, Scheme 2)

145. 2-(4-Pyridyl)-4-[[4″-(N-methyl-N-propylamino)methyl]phenyl]thiazole(I, R₁R²-Ar=4-py, R₃=propyl, R₄=Me, R⁵=H, p=1, V=N)

146. 2-(4-Pyridyl)-4-[(4″-hydroxymethyl)phenyl]thiazole is prepared byfollowing the above procedure in Example 2.

147. A solution of methanesulfonylchloride (0.75 mL, 9.11 mmol) in THF(5 mL) is added with stirring to an ice-cold solution of the abovealcohol (0.83 g, 3.09 mmol) in THF (70 mL) containing Et₃N (0.92 mL,9.11 mmol). After the addition is over the reaction mixture is allowedto warm up to room temperature and eventually refluxed for 2 h tocomplete the reaction. The reaction mixture is cooled and filtered. Theresidue is washed with CHCl₃ and dried to give the desired compound as ayellow solid (0.45 g).

148.¹H NMR (DMSO_(d6)) δ2.35 (s, 3 H), 4.84 (s, 2 H), 7.59 (d, 2 H),8.13 (d, 2 H) 8.43 (d, 2 H), 8.95 (d, 2 H).

149. A solution of the above mesylate (0.45 g, 1.3 mmol) andN-methyl-N-propyl amine (0.33 mL, 3.25 mmol) in THF (50 mL) is heated at55° C. for 18 h. The reaction mixture is stripped and flashchromatographed (SiO₂, CHCl₃/MeOH 5%) to give 0.238 g of title compound.

150.¹H NMR (CHCl₃): δ0.86 (t, 3 H), 1.38-1.60 (m, 2 H), 2.13 (s, 3 H),2.30 (t, 2 H), 3.49 (s, 2 H), 7.40 (d, 2 H), 7.95-8.04 (dd, 4 H), 8.32(s, 1 H), 8.75 (d, 2 H).

151. It was converted to dihydrochloride salt, mp. 192-195 ° C.

152. Additional examples are shown in Table I.

EXAMPLE 3

153. (Process 3, Scheme 3)

154.2-(4′-methoxyphenyl)-4-[4Ó-[2-(N,N-dimethylamino)-ethyl]phenyl]thiazole(II: R¹=H, R²=4-CH₃O, R³=R⁴=CH₃, R⁵=H, R⁶=H, V=N, p=2)

155. To a solution of 4′-(2-chloroethyl)acetophenone (5.00 g, 27.37mmol) and aluminum chloride (0.30 g, 2.73 mmol) in anhydrous diethylether (75 ml) is added bromine (4.37 g, 27.37 mmol) dropwise. After 18hours the solution is concentrated and the residue is taken up in CHCl₃(75 ml) and washed with water (75 ml). The organic layer is dried overMgSO₄ and concentrated to yield 7.91 g crude bromo product as a dark oilwhich is used as is without further purification.

156. A mixture of α-bromo-4′-(2-chloroethyl)acetophenone, (1.56 g, 5.98mmol) and 4-methoxythicbenzamide (1.00 g, 5.98 mmol) is heated to refluxin EtOH (25 ml) for 2 hours. The mixture is then cooled to 5° C. and theprecipitate filtered and dried to yield2-(4Õ-methoxyphenyl)-4-[4Ó-(2-chloroethyl)phenyl]thiazole (0.90 g, 46%).

157. A solution of2-(4′-methoxyphenyl)-4-[4Ó-(2-chloroethyl)phenyl]-thiazole (0.30 g, 0.71mmol) and excess (2 ml) dimethyl amine/EtOH solution (19% w/w) in THF(10 ml) is placed into a sealed reaction vessel and heated to 80° C. for20 hours. The solution is then concentrated and the residue taken up inCHCl₃(20 ml) and washed with saturated NaHCO₃ (20 ml). The organic layeris dried over MgSO₄ and concentrated to yield an oil which is purifiedon a silica gel column eluting with 10% MeOH/CHCl₃ to yield the titlecompound as an off white solid (90mg, 37%).

158.¹H NMR (CDCl₃) δ2.33 (s, 6H), 2,60 (m, 2H), 2.80 (m, 2H), 3.86(s,3H), 6.97 (d, 2H), 7.27 (d, 2H), 7.35 (s, 1H), 7.89 (d, 2H) , 7.97(di 2H) .

159. Additional examples are shown in Table I.

EXAMPLE 4

160. (Process 4, Scheme 4)

161.2-(4′-Fluorophenyl)-4-[4′-[3-(N,N-dimethylamino)-propyl]phenyl]thiazole(II: R¹=H, R²=4-F, p=3, V=N, R³=R⁴=CH₃)

162. To a solution of p-fluorothiobenzamide (0.39 g, 2.5 mmol) in 20 mLof abs. EtOH is added 2,4′-dibromoacetophenone (0.7 g, 2.5 mmol) all atonce. The reaction mixture is stirred at room temperature for 3 hoursand then chilled in ice bath. The precipitate is collected byfiltration, washed with cold EtOH (5 ml×2) and dried in vacuum to give2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole as a white fluffycrystaline solid (1.55 g, 93%). mp.158-9° C.

163.¹H NMR (CDCl₃): δ7.16 (t, 2H), 7.47 (s, 1H), 7.58 (d, 2H), 7.87 ()d,2H), 8.02 (m, 2H).

164. In a 100 ml flask is placed triphenylphosphine (80 mg, 10 %) ,PdCl₂ (40 mg, 5 %) and 2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole(0.98 g, 2.9 mmol) in 20 mL of diethylamine. After stirring for 15 minunder N₂ atmosphere, CuI (30 mg, 5 %) and 1-dimethylamino-2-propyne(0.27 g, 3.18 mmol) in 20 ml of acetonitrile are added to the mixture.After 18 h of heating, the solvent is evaporated under reduced pressureand the residue is filtered through silica gel pad (50 g) using CHCl₃(400 mL) and 2% MeOH in CHCl₃(400 mL). A large portion of unreacted2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole is recovered afterremoval of chloroform filtrate (0.55 g, 56%). The second part of thefiltrate (2% MeOH in CHCl₃) is concentrated and the residual solid isthen purified over silca gel column eluting with 2% MeOH in CHCl₃.2-(4′-fluorophenyl)-4-[4′-(3-dimethylamino-2-propyn-1-yl)phenyl]thiazoleis obtained after concentration and trituration with hexane (0.25 g, 27%yield), mp. 98-9° C.

165.¹H NMR (CDCl₃) δ2.39 (s, 6H) , 3.50 (s, 2H), 7.16 (t, 2H), 7.48 (s,1H), 7.51 (d, 2H), 7.93 (d, 2H), 8.03 (m, 2H).

166. A warm solution of2-(4′-fluorophenyl)-4-[4′-(1-dimethylamino-2-propyn-3-yl)phenyl]thiazole(0.2 g, 0.6 mmol) in abs. EtOH (20 mL) containing a catalytic amount ofpalladium on activated carbon (5 %, 20 mg) is shaked under hydrogenatomsphere (30 psi) for 2 h. After removal of the catalyst byfiltration, the filtrate is concentrated to give2-(4′-fluorophenyl)-4-[4′-(3-N,N-dimethylaminopropyl)phenyl]thiazole asdesired product (0.18 g, 89 %)

167.¹H NMR (CDCl₃): δ1.65 (m, 2H), 2.24 (s, 6H), 2.32 (t, 2H), 2.69 (t,2H), 7.14 (t, 2H), 7.27 (d, 2H), 7.40 (s, 1H), 7.89 (d, 2H), 8.02 (m,2H).

168. Additional examples are shown in Table I.

EXAMPLE 5

169. (Process 5, Scheme 5)

170. 2 -(4′-Chlorophenyl 4-[[4-(N-pentyl)aminomethyl]phenyl]thiazole(VI: R₁=H, R₂=4-Cl, R₃=n-pentyl, R⁴=H)

171. To a boiling solution of methenamine (1.1 g, 7.85 mmol) in CCl₄ (80mL) is added dropwise a solution of2-(4′-chlorophenyl)-4-[4′-bromomethyl)phenyl]thiazole (Scheme 1; 2.6 g,7.13 mmol) in CHCl₃ (40 mL). The reaction mixture is refluxed for 3 hunder N₂ and cooled. The white precipitate is filtered and the residuewashed with a small volume of CHCl₃ and air dried to give the quaternarysalt (2.7 g). Conc. HCl (4 mL) is added dropwise with stirring to asuspension of the above salt (2.7 g) in EtOH (30 mL) and the reactionmixture is heated to reflux for 3 h. It is cooled, filtered and theresidue is washed with a small volume of EtOH and dried to give thedesired amine hydrochloride (1.97 g). mp. >320° C. ¹H NMR (DMSO-d₆):δ4.05 (s, 2 H), 7.43-7.63 (m, 4 H), 7.95-8.13 (m, 5 H).

172. To an aqueous suspension of the above salt is added an aqueoussolution of NaOH (6 N) to pH 12, and the free base is extracted withCH₂Cl₂. The extract is dried and evaporated to give the correspondingamine, 2-(4′-chlorophenyl)-4-[4-(aminomethyl) phenyl]thiazole (1.4 g).

173.¹H NMR (DMSO-d₆): δ3.75 (s, 2 H), 7.43 (d, 2 H), 7.60 (d, 2 H), 7.98(d, 2 H), 8.06 (d, 2 H), 8.16 (s, 1 H).

174. A solution of trifluoroacetic anhydride (0.85 mL, 6 mmol) in THF (5mL) is added dropwise to a solution of the above amine (1.4 g, 4.7 mmol)in THF (15 mL) and the reaction mixture stirred for 18 h at roomtemperature. The THF is evaporated and the residue triturated with asmall volume of ether. The solid is filtered, washed with hexane, anddried to give2-(4′-chlorophenyl)-4-[4′-trifluoroacetylamino-methyl)phenyl]thiazole(1.56 g).mp.174-175° C.

175.¹H NMR (CDCl₃): δ4.58 (d, 2 H), 6.58 (br s, 1 H), 7.30-7.48 (m, 4H), 7.51 (s, 1 H), 7.91-8.05 (m, 4 H).

176. A solution of the above compound (0.59 g, 1.48 mmol) in DMF (5 mL)is added to a slurry of NaH (60%, 70 mg, 1.77 mmol) in DMF (2 mL) undernitrogen. The reaction mixture is stirred at room temperature until thegas evolution ceased (^(˜)1 h). n-Iodopentane (0.5 g, 2.5 mmol) isadded, and the reaction mixture is heated at 100° C. (oil bath) for 3 h.The reaction mixture is cooled, poured into water (50 mL) and theorganic material is extracted with EtOAc. The EtOAc layer is washed withbrine, dried and stripped to yield a solid which is chromatographed(SiO₂, 0-5% MeOH/CH₂Cl₂) to give the desired compound (0.5 g).

177.¹H NMR (CDCl₃): δ0.88 (t, 3H), 1.10-1.41 (m, 4H), 1.45-1.80 (m, 2H),3.34 (t, 2H), 4.68 (d, 2H), 7.33 (d, 2H), 7.40-7.60 (m, 3H), 7.92-8.22(m, 4H).

178. A solution of the above trifluoroacetylamide (1.05 g, 2.25 mmol)and aqueous KOH (25%, 6 mL, 2.68 mmol) in acetone (30 mL) is heatedunder reflux for 18 h. Acetone is distilled, and the residue ispartitioned between water(15 mL) and EtOAc (25 mL). The organic layer isseparated and the aqueous layer is extracted with EtOAc (3×20 mL). Thecombined organic extract is washed with brine, dried, andchromatographed (SiO₂, 0-5% MeOH/CH₂Cl₂) to give the title compound (0.8g)₁ mp. 70-72° C.

179.¹H NMR (CDCl₃): 0.88 (t, 3 H), 1.12-1.45 (m, 4 H), 1.45-1.80 (m, 2H), 2.64 (t, 2 H), 3.55(br s, 1 H), 3.85 (s, 2 H), 7.32-7.52 (m, 5 H),7.83-8.13 (m, 4 H).

EXAMPLE 5a

180. 2-(4′-Chlorophenyl-4-[[4′-(N-cyclopropyl,N-methyl)-aminomethyl]phenyl]thiazole (VI: R₁=H, R₂=4-Cl, R₃=c-propyl,R₄=Me)

181. Iodomethane (0.1 mL, 2.1 mmol) is added to a stirred mixture of2-(4′-chlorophenyl-4-[[4′-(N-cyclopropyl)aminomethyl]phenyl]thiazole(prepared as in Example 5) (0.2 g, 0.6 mmol) and anhydrous K₂CO₃ (0.2 g,1.4 mmol) in THF (15 mL). It is stirred for 16 h and filtered, Theresidue is washed with CH₂Cl₂, the washings and the filtrate areevaporated, and the residual oil is chromatographed (SiO₂, 0-2%MeOH/CH₂Cl₂) to give 50 mg of the title compound.

182. Additional examples are shown in Table I, herein below.

EXAMPLE 6

183. (Process 6, Scheme 6)

184. 2-(4′-Cyanophenyl-4-[[4′-(N,N-dimethyl)aminomethyl]phenyl]thiazole(VI: R₁=H, R₂=4-CN, R₃=R₄=Me)

185. To a mixture of 4′-methylacetophenone (30 g, 0.22 mol) and NBS(39.9 g, 0.22 mol) in CCl₄ (200 mL) is added 0.2 g of benzoylperoxideand the reaction mixture is heated under reflux for 6 h. Additionalbenzoylperoxide (0.2 g) is added and the mixture refluxed for 16 h. Itis cooled and filtered. The filtrate is stripped to yield an oil (47.9g). ¹H NMR indicates ^(˜)75% of the desired bromide which is used as isfor the next step.

186. Dimethylamine (19% in EtOH, 21.2 g, 0.47 mol) is added dropwise toa solution of the above bromide (47.8 g, 15 0.22 mol) in CH₂Cl₂(100 mL)at 0° C. with stirring. After the addition is over the ice bath isremoved, and the solution is stirred for 16 h at room temperature. Thesolvent is evaporated and the residue is taken up in CHCl₃ Thechloroform solution is washed successively with saturated NaHCO₃, brine,dried and stripped. The residue is chromatographed (SiO₂, 2-10%MeOH/CH₂Cl₂) to give 15 g of 4′-(N,N-dimethylamino)methylacetphone. Theamine is converted to the corresponding HCl salt.

187. Bromine (1.36 mL; 26.5 mmol) is added dropwise to a solution of theabove HCl salt (5.6 g, 26.5 mmol) in CHCl₃ (60 mL) at 0° C. withstirring. The reaction mixture is stirred at room temperature for 2 hand the solvent evaporated yielding a brown solid (9 g).

188.¹H NMR (CDCl₃): δ2.81 (s, 6 H), 4.26 (s, 2 H), 4.44 (s, 2 H), 7.89(d, 2 H), 8.07 (d, 2 H)

189. A mixture of the above phenacyl bromide (1.54 g, 4.57 mmol) and4-cyanothiobenzamide (0.74 g, 4.57 mmol) in EtOH (15 ml) is heated underreflux for 2 h. It is cooled and filtered to give a yellow solid (1.17g). The solid is partitioned between CHCl₃ and saturated NaHCO₃solution, The organic layer is separated, washed with brine, dried andevaporated to give 0.77 g of a solid. It is purified via columnchromatography (SiO₂, 0-2% MeOH/CH₂Cl₂) to give 0.46 g of the titlecompound, mp. 121-122° C.

190.¹H NMR (CDCl₃): δ2.37 (s, 6 H), 3.47 (s, 2 H), 7.42 (d, 2 H), 7.57(s, 1 H), 7.77 (d, 2H), 7.92 (d, 2 H), 8.13 (d, 2 H).

EXAMPLE 6a

191.2-(4′-Fluorophenyl-4-[[[4′-(N,N-dimethyl)aminomethyl]-3Õ-nitro]phenyl]thiazole(II: R₁=H, R₂=4-F, R₃=R₄=Me, R₆=H, R₅=3-NO₂, V=N, p=1)

192. Replacing 4′-methylacetophenone with 4′-methyl-3′-nitroacetophenoneand following the above procedure the compound4′-(N,N-dimethylamino)methyl-3′-nitroacetophenone is obtained. This isconverted to the HCl salt and brominated to giveα-bromo-4′-methyl-3′-nitroacetophenone.

193. A mixture ofα-bromo-4′-(N,N-dimethylaminomethyl)-3′-nitroacetophenone (2.38 g, 6.23mmol) and 4-fluorothiobenzamide (0.97 g, 6.23 mmol) in EtOH (150 mL) isheated under reflux for 6 h. EtOH is stripped and the residue is takenup in EtOAc. The EtOAc solution is washed successively with saturatedNa₂CO₃ and brine, dried, and stripped. The residue is triturated withisopropyl alcohol and filtered to give 1.37 g of the title compound, mp.112° C.

194.¹H NMR (CDCl₃) δ2.25 (s, 6 H), 3.75 (s, 2 H), 7.17 (t, 2 H), 7.57(s, 1 H), 7.69 (d, 1H), 7.98-8.18 (m, 3 H), 8.45 (d, 1 H).

EXAMPLE 6b

195. 2-(4′-Fluorophenyl-4-[[[4′-(N,N-dimethyl)aminomethyl]-3′-amino]phenyl]thiazole(II: R₁=H, R₂=4-F, R₃=R₄=Me, R₆=H, R₅=NH₂, V=N, p=1)

196. A solution of the above nitro compound (Example 6a, 0.65 g) in EtOH(80 mL) and HCl (0.2 mL) is reduced under catalytic condition (5% Pd/C,250 mg). After the reduction is complete (18 h) the catalyst is filteredand the filtrate is evaporated to dryness. The residue is partitionedbetween CH₂Cl₂ and saturated Na₂CO₃. The organic layer is washed withwater, dried and stripped to give 0.47 g of the title compound, mp.108-109° C.

197.¹H NMR (CDCl₃): δ2.21 (s, 6 H) , 3.45 (s, 2 H) , 7.05 (t, 2 H), 7.14(s, 1 H), 7.18-7.23 (d, 1 H), 7.31 (d, 1 H), 7.40 (s, 1 H), 7.97-8.08(dd, 2 H).

EXAMPLE 6c

198. 2-(4′-Fluorophenyl-4-[[[4′-(N,N-dimethyl)aminomethyl]-3′-acetylamino]phenyl]thiazole(II: R₁=H, R₂=4-F, R₃=R₄=Me, R₆H, R₅=NHCOCH₃, V=N, p=1)

199. Acetic anhydride (0.4 mL) is added to a solution of the above am,ne(Example 6b,0.47 g) in anhydrous THF (10 mL) and the solution is stirredat room temperature for 18 h. THF is evaporated and the residue is takenup in CHCl₃. The CHCl₃ solution is washed thoroughly with water, driedand stripped to yield a soft solid. It is triturated with ether andfiltered to give 0.21 g of the title compound as a white solid, mp.128.5° C.

200.¹H NMR (CDCl₃) δ2.15 (s, 3 H), 2.30(s, 6 H), 3.50 (s, 2 H),7.10-7.20 (m, 3 H), 7.50 (s, 1 H), 7.65-7.75 (d, 1 H), 8.00-8.10 (dd, 2H), 8.80 (s, 1 H), 10.75 (br s, 1 H).

201. Additional examples are shown in Table I, herein below.

EXAMPLE 7

202. (Process 7, Scheme 7)

203. 2-(3′-Nitrophenyl-4-[[[4′-(N,N-dimethylamino)methyl]-3′-hydroxy]phenyl]thiazole(II: R₁=H, R₂=3-NO₂, R₃=R₄CH₃, R₅=3-OH, R₆=H, V=N, p=1)

204. A mixture of 3-nitrobenzenethioamide (2.73 g, 15 mmol) and3-methoxy-α-[bromoacetophenone (3.43 g, 15 mmol) in EtOH (30 mL) isheated under reflux for 18 h. It is cooled and filtered to give 4 g of2-(3′-nitrophenyl)-4[(3′-methoxy)phenyl]thiazole as a yellow solid, mp.122-123° C.

205.¹H NMR (CDCl₃): δ3.94 (s, 3 H), 6.90-7.01 (dd, 1 H), 7.32-7.48 (t, 1H), 7.50-7.75 (m, 4 H), 8.22-8.45 (dd,dd 2 H), 8.90 (dd, 1 H).

206. To an ice-cold solution of the above methylether (0.77 g, 2.46mmol) in CH₂Cl₂ (10 mL) is added a solution of BBr₃ in CH₂Cl₂ (1M, 4.9mL). The solution is stirred at 0° C. for 0.5 h and then at roomtemperature for 18 h. It is quenched with 12 mL of water, and themixture is stirred for 0.5 h and filtered. The residue is washedthoroughly with water, followed by ether and dried to give 0.55 g of2-(3′-nitrophenyl)-4[(3′-hydroxy)phenyl]thiazole.

207. A mixture of the above hydroxy compound (0.55 g, 1.93 mmol),p-formaldehyde (0.3 g), (Me)₂NH/EtOH (19%, 2.2 mL) in EtOH (7 mL) isrefluxed for 8 h. EtOH is evaporated, and the residue is poured intowater, and the solution is taken up in CH₂Cl₂. The organic layer iswashed with brine, dried, stripped, and the residue chromatographed(SiC₂, MeOH/CH₂Cl₂2%) to yield 0.15 g of the title compound, mp.157-160° C.

208.¹H NMR (CDCl₃): δ2.32 (s, 6 H), 3.67 (s, 2 H), 7.00-7.01 (dd, 1 H),7.40-7.48 (m, 2 H), 7.53 (s, 1 H), 7.65 (t, 1 H), 8.22-8.45 (dd,dd 2 H),8.85 (m, 1 H).

209. Additional examples are shown in Table I, herein below.

EXAMPLE 8

210. (Process 8, Scheme 8)

211.5-(4′-Fluorophenyl)-3-[4″-(N-methyl-N-allylaminomethyl)-phenyl]-1,2,4-thiadiazole(III: R¹=H, R²=4-F, R³=CH₃, R⁴=allyl, R⁵=H, V=N, p=1)

212. To a solution of p-tolunitrile (10.1 g, 86.21 mmol) in 100 mlCHCl₃:MeOH (1:1) cooled to 5° C. in an ice-water bath is bubbled HCl for1 hour to reach saturation. The solution is stirred at 10° C. for 43hours, then concentrated under reduced pressure to yieldp-methylbenzimidate hydrochloride as pale yellow crystals (15.98g, 99%).

213.¹H NMR (CDCl₃) δ2.44 (s, 3H), 4.52 (s, 3H), 7.36 (d, 2H), 8.29 (d,2H).

214. To a solution of p-methylbenzimidate hydrochloride (8.00 g, 43.09mmol) in MeOH (100 ml) is added NH₃/MeOH solution (2.68M, 24.12 ml,64.64 mmol). Upon the addition of the NH₃, the mixture has a pH around8.5. To this solution is added ammonium chloride (2.30 g, 43.09 mmol).The reaction mixture is stirred at room temperature for 20 hours, thencooled in refrigerator and the precipitate is removed by filtration. Themother liquor is concentrated to yield the crude product which is takenup in a limited amount of cold EtOH and the white precipitate isfiltered. The beige filtrate is concentrated to yieldp-methylbenzamidine hydrochloride as an off-white solid (7.15g, 97%).

215.¹H NMR (DMSO_(d6)) δ2.41 (s, 3H), 7.43 (d, 2H), 7.78 (d, 2H)9.24-9.39 (broad d, 3H).

216. To a mixture of p-methylbenzamidine hydrochloride (5.1 g, 30.0mmol) in CHCl₃ (100 ml) is added triethyl amine (15.12 g, 20.9 ml, 150.0mmol) and cooled to 5° C. in an ice-water bath. To the mixture is slowlyadded perchloromethyl mercaptan (95%, 6.16 g, 31.5 mmol) in CHCl₃(10 ml)over 1 hour. The yellow solution is allowed to warm up to roomtemperature. After 2 hours the mixture is washed with water (100 ml×2)and brine (100 ml). The organic layer is dried over MgSO₄ and thesolvent is removed under reduced pressure to yield a brown oil. The oilis purified on a bed of silica gel, eluting with 1:1 CHCl₃:hexanes toyield 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole as a yellow solid (2.78g,44%).

217.¹H NMR (CDCl₃) : δ2.41 (s, 3H), 7.30(d, 2H), 8.13 (d, 2H).

218. A mixture of 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole (0.50 g, 2.37mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) chloridecatalyst (1.41g, 2.61 mmol) in anhydrous THF (20 ml) is cooled in anice-water bath. To this mixture is added slowly 4-fluorophenyl-magnesiumbromide (1.0M in THF, 2.5 ml, 2.49 mmol) with exclusion of both moistureand oxygen. The mixture is allowed to warm to room temperature andstirred for 18 hours under N₂. The mixture is filtered through celiteand concentrated. The residue is taken up in CHCl₃ (50 ml) and washedwith brine (50 ml×2). The organic layer is dried over magnesium sulfateand concentrated. The residue is purified on a silica gel column,eluting with 3:7 CHCl₃:hexanes to yield5-(4′-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole (0.20 g, 31%).

219.¹H NMR (CDCl₃) δ2.43 (s, 3H), 7.21-7.32 (m, 4H), 8.06 (m, 2H), 8.24(d, 2H).

220. To a solution of 5-(4′-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole(0.16 g, 0.59 mmol) in CCl₄ (20 ml) is added NBS (0.11 g, 0.59 mmol) andthe mixture is heated to reflux for 36 hours. The mixture is cooled toroom temperature and filtered through celite. The mother liquor isconcentrated. The residue is taken up in chloroform (30 ml) amd washedwith water (30 ml). The organic layer is dried over MgSO₄ andconcentrated to yield5-(4′-fluorophenyl)-3-(p-bromomethylphenyl)-1,2,4-thiadiazole, (0.22 g)as crude product which is used as is without further purification.

221.¹H NMR (CDCl₃): δ4.55 (s, 2H), 7.19 (d, 2H), 7.54 (d, 2H), 8.06 (m,2H), 8.35 (d, 2H).

222. To a solution of5-(4′-fluorophenyl)-3-(4″-bromomethylphenyl)-1,2,4-thiadiazole (0.19 g,0.54 mmol) in chloroform (15 ml) is added slowly N-methyl-allylamine(0.14 g, 1.62 mmol) in chloroform (5 ml). The solution is stirred atroom temperature for 12 hours and washed with water (30 ml). The organiclayer is dried over K₂CO₃ and concentrated. The resulting oil ischromatographed on a silica gel column, eluting with ethylacetate:hexanes (30:60) to yield the title compound as an oil. (0.10 g,55%)

223.¹H NMR (CDCl₃): δ2.23 (s, 3H), 3.05 (d, 2H), 3.57 (s, 2H), 5.12-5.30(m, 2H), 5.85-6.05 (m, 1H), 7.19 (d, 2H), 7.45 (d, 2H), 8.07 (m, 2H),8.32 (d, 2H).

224. Additional examples are shown in Table I, herein below.

EXAMPLE 9

225. (Process 9, Scheme 9)

226. 1,3,4-Thiadiazoles and 1,3,4-Oxadiazoles

227.2-(3′-Nitrophenyl)-5-[4″-(N,N-dimethylaminomethyl)phenyl]-1,3,4-thiadiazole(IV: R¹=H, R²=3-NO₂, R³=R⁴=CH₃, R⁵=H, V=N, p=1)

228. To a solution of 3-nitrobenzhydrazide (2.16 g, 11.92 mmol) inpyridine (40ml) cooled to 0° C. in an ice bath is added dropwisep-toluoyl chloride (1.94 g, 11.92 mmol). The mixture is allowed to warmto room temperature and stirred for 12 hours. The mixture is quenchedwith 350 mL of water and stirred for thirty minutes. The precipitate isfiltered and dried in a vacuum oven to yield1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine as a pale yellowsolid. (2.94 g, 82%).

229.¹H NMR (DMSO_(d6)) δ2.40 (s, 3H), 7.35 (d, 2H), 7.86 (d, 2H), 7.87(t, 1H), 8.37 (d, lH), 8.45 (d, 1H), 8.76 (s, 1H), 10.58 (s, 1H), 10.90(s, 1H).

230. A mixture of 1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine(1.40 g, 4.68 mmol) and Lawsson's Reagent (0.95 g, 2.34 mmol) in benzene(25ml) is slowly heated to 60° C. After 3 hours the solution isconcentrated, quenched with 35 ml of water and heated to reflux for 12hours. The mixture is then cooled to room temperature and the precpitateis collected by filtration. The precipitate is then taken up inchloroform (100 ml) and the insoluble portion is removed by filtration.The filtrate is then dried over MgSO₄ and concentrated to yield2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole as a pale yellow solid.(0.67 g, 48%).

231.¹H NMR(CDCl₃): δ2.45 (s, 3H), 7.35 (d, 2H), 7.73 (t, 1H), 7.92 (d,2H), 8.38 (t, 2H), 8.81 (s, 1H).

232. To a solution of 2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole(0.66 g, 2.22 mmol) in CCl₄ (75 ml) is added NBS (0.43 g, 2.44 mmol) andrefluxed for 12 hours. The mixture is then concentrated and the residueis taken up in chloroform (50 ml) and washed with saturated NaHCO₃ (50ml) and brine (50 ml). The organic layer is dried over MgSO₄ andconcentrated to yield2-(3′-nitrophenyl)-5-(p-bromomethylphenyl)-1,3,4-thiadiazole as a tansolid. (0.69 g, 83%).

233.¹H NMR (CDCl₃) δ4.51 (s, 2H) , 7.55 (d, 21), 7.72 (t, 1H), 8.01 (d,2H), 8.39 (t, 2H), 8.80 (s, 1H).

234. To a suspension of2-(3′-nitrophenyl)-5-(p-bromomethylphenyl)-1,3,4-thiadiazole (0.69 g,1.83 mmol) in warm EtOH (25 ml) is added excess dimethyl amine/EtOHsolution (^(˜)19% w/w, 3 ml) and stirred at room temperature. After 12hours the solution is concentrated and the residue is taken up inchloroform (50 ml) and washed with saturated NaHCO₃ (50 ml) and brine(50 ml). The organic layer is dried over K₂CO₃ and concentrated to yielda brown solid which is chromatographed on a silica gel column, elutingwith 10% MeOH/CHCl₃ to yield the title compound as a tan solid. (0.26 g,37%)

235.¹H NMR (CDCl₃): δ2.29 (s, 6H), 3.50 (s, 2H), 7.50 (d, 2H), 7.72 (t,1H), 7.97 (d, 2H), 8.39 (t, 2H), 8.82 (s, 1H).

EXAMPLE 9a

236.2-(3′-Nitrophenyl)-5-[4″-(N,N-dimethylaminomethyl)phenyl]-1,3,4-oxadiazole(V: R¹=H, R²=3-NO₂, R³=R⁴CH₃, R⁵=H, V=N, p=1)

237. A suspension of 1-[(4-methylbenzoyl)]-2-(3-nitrobenzoyl)hydrazine(1.37 g, 4.58 mmol) in 20 ml thionyl chloride is heated to reflux for 12hours. The solution is concentrated and the residue is taken up inchloroform (50 ml) and washed with water (50 ml) and brine (50 ml). Theorganic layer is dried over MgSC₄ and concentrated to yield2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-oxadiazole as a yellow solid. (1.12g, 87%).

238.¹H NMR (CDCl₃)δ2.47 (s, 3H), 7.39 (d, 2H), 7.76 (t, 1H), 8.07 (d,2H), 8.42 (d, 1H), 8.80 (d, 1H), 8.95 (s, 1H).

239. To a solution of 2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-oxadiazole(1.00 g, 3.56 mmol) in CCl₄ (25 ml) is added NBS (0.43 g, 3.74 mmol) andthe mixture is heated to reflux. After 24 hours the solution isconcentrated and the residue taken up in chloroform (100 m) and washedwith saturated NaHCO₃ (50 ml) and brine (50 ml). The organic layer isdried over MgSO₄ and concentrated to yield2-(3′-nitrophenyl)-5-[(p-bromomethyl)phenyl]-1,3,4-oxadiazole as a tansolid. (0.69 g, 83%).

240.¹H NMR (CDCl₃) δ4.55 (s, 2H), 7.59 (d, 2H), 7.78 (t, 1H), 8.16 (d,2H), 8.45 (d, 1H), 8.52 (d, 1H), 8.96 (s, 1H).

241. To a suspension of 2-(3′-nitrophenyl)5-[-(p-bromomethyl)phenyl]-1,3,4-oxadiazole (0.50 g, 1.39 mmol) in warmEtOH (25 ml) is added excess dimethyl amine/EtOH solution (^(˜)199 w/w,3 ml) and stirred at room temperature for 12 hours. The solution is thenconcentrated and the residue taken up in chloroform (30 ml) and iswashed with saturated NaHCO₃ (30 ml) and brine (30 ml). The organiclayer is dried over K₂CO₃ and concentrated to yield a brown oil which ischromatographed on a silica gel column eluting with 10% MeOH/CHCl₃ toyield the title compound as a tan solid. (0.22 g, 49%).

242.¹H NMR (CDCl₃) δ2.25 (s, 6H), 3.52 (s, 2H), 7.54 (d,2H), 7.77 (t,1H), 8.12 (d, 2H), 8.40 (d, 1H), 8.54 (d,1H), 8.95 (s, 1H).

243. By following the process schemes described in the precedingExamples the following compurnds have also been prepared. TABLE IProcess Example Scheme Name 1d 1 2-(4′-fluorophenyl)-4-[4″-(N-methyl-N-(2-fur- furyl)aminomethyl)phenyl]thiazole 1e 12-(4′-fluorophenyl)-4-[4″-(N-butyn-1- oxymethyl)phenyl]thiazole 1f 12-(4′-fluorophenyl)-4-(4″-(N-methyl-N-propargylaminomethyl)phenyl]thiazole 1g 12-(4′-chlorophenyl)-4-[4″-(N-methyl-N- allylaminomethyl)phenyl]thiazole1h 1 2-(4′-nitrophenyl)-4-[4″-(N-methyl-N-allylaminomethyl)phenyl]thiazole 1i 1 2-(4′-fluorophenyl)-4-[4″-(2-(t-butyoxy)ethoxymethyl)phenyl]thiazole 1j 12-(2′-nitrophenyl)-4-[4″-(N-methyl-N- allylaminonomethyl)phenyl]thiazole1k 1 2-(3′-nitrophenyl)-4-[4″-(N-methyl-N-allylaminomethyl)phenyl]thiazole 1l 1 2-(4′-fluorophenyl)-4-[4″-(2-propenyloxymethyl)phenyl]thiazole 1m 1 2-(4′-fluorophenyl)-4-[4″-(N-cyclopropylaminomethyl)phenyl]thiazole 1n 12-(4′-fluorophenyl)-4-[4″-(N- allylaminomethyl)phenyl]thiazole 1o 12-(4′-nitrophenyl)-4-[4″-(N-methyl-N- propylaminomethyl)phenyl]thiazole1p 1 5-bromo-2-(4′-nitrophenyl)-4-[4″-(N- methyl-N-allyl-aminomethyl)phenyl]thiazole 1q 1 2-[4′-(1H-pyrrol-1-yl)phenyl]-4-[4″-(N-methyl-N- propylmethyl)phenyl]thiazole 1r 12-(4′-aminophenyl)-4-[4″-(N-methyl-N- propylmethyl)phenyl]thiazole 1s 12-(4′-nitrophenyl)-4-[4″- (diallylaminomethyl)phenyl]thiazole 1t 12-(4′-nitorophenyl)-4-[4″- (dipropylaminomethyl)phenyl]-thiazole 6d 62-(4′-trifluoromethylphenyl)-4-[4″-(N- methyl-N-allylamino-methyl)phenyl]thiazole 2c 2 2-(4′-pyridyl)-4-[4″-(N-methyl-N-propylaminomethyl)phenyl]thiazole 6e 62-(4′-cyanophenyl)-4-[4″-(N-methyl-N- propylaminomethyl)phenyl]-thiazole1u 1 2-(4′-chlorophenyl)-4-[4″-(N-methyl-N-(2-dimethylaminoethyl)aminomethyl)- phenyl]thiazole 6f 62-(2′-fluoro-4′- trifluoromethylphenyl)-4-[4″-(N- methyl-N-propylamino-methyl)phenyl]thiazole 1v 1 2-(4′-nitrophenyl)-4-[4″-(diisopropylaminomethyl)- phenyl]thiazole 1x 1 2-(4′-nitrophenyl)-4-[4″-(dimethylaminomethyl)phenyl]thiazole 1y 12-(2′-fluorophenyl)-4-[4″-(N-methyl-N- allylaminomethyl)phenyl]thiazole1z 1 2-(4′-trifluoromethoxyphenyl)-4-[4″- (N-methyl-N-allylaminomethyl)-phenyl]thiazole 1aa 1 2-(3′-nitrophenyl)-4-[4″-(dimethylaminomethyl)phenyl]-thiazole 1bb 12-(3′-nitrophenyl)-4-[4″-(N-methyl-N- propylaminomethyl)phenyl]thiazole1cc 1 2-(4′-nitrophenyl)-4-[4″-[(2- diethylaminoethoxy)-methyl]phenyl]thiazole 1dd 1 2-(3′-nitrophenyl)-4-[4″-(N-methyl-N-(2-methoxyethyl)aminomethyl)- phenyl]thiazole 6g 62-(4′-iodophenyl)-4-[4″-(N-methyl-N- propylaminomethyl)phenyl]-thiazole1ee 1 2-(4′-chlorophenyl)-4-[4″-(N-methyl-N-(2-hydroxyethyl)aminomethyl)- phenyl]thiazole 6h 64-[4′-methyl-N-propylamino- methyl)phenyl]-2-(pyrid-3″-yl)thiazole 1ss 12-(4′-chlorophenyl)-4-[4″-[[2- (diethylamino)ethyl]-thiomethyl]phenyl]thiazole 6i 6 2-[4′-(trimethylsilylethynyl)phenyl]-4-[4″-(N-methyl-N-propylamino- methyl)phenyl]thiazole 6j 62-(4′-ethynylphenyl)-4-[4″-N-methyl-N- propylaminomethyl)phenyl]thiazole1ff 1 2-(4′-chlorophenyl)-4-[4″-[(4- ethylpiperazin-1-yl)methyl]-phenyl]thiazole 6k 6 2-(4′-methoxy-3′-nitrophenyl)-4-[4″-(N-methyl-N-propylamino- methyl)phenyl]thiazole 6l 62-(4′-methoxy-3′-nitrophenyl)-4-[4″-(dimethylaminomethyl)phenyl]thiazole 1gg 1 2-(4′-chlorophenyl)-4-[4″-[[3(dimethylamino)propyl]aminomethyl]- phenyl]thiazole 1hh 12-(3′-nitrophenyl)-4-[4″-(N- hydroxymethylaminomethyl)- phenyl]thiazole1ii 1 2-(3′-nitrophenyl)-4-[4″-(N-methyl-N- (2-phenylethyl)aminomethyl)-phenyl]thiazole 8a 8 5-(4′-fluorophenyl)-3-[4″-(N-methyl-N-allylaminomethyl)phenyl]-1,2,4- thiadiazole 8b 85-phenyl-3-[4″-(N-methyl-N- allylaminomethyl)phenyl]-1,2,4- thiadiazole1tt 1 2-(4′-chlorophenyl)-4-[4″-(N-methyl-N-(2-N-methylaminoethyl)-amino- methyl)phenyl]thiazole 5c 52-(4′-chlorophenyl)-4-[4″-(N- octylaminoethyl)amino-methyl)phenyl]thiazole 6n 6 2-(3′-cyanophenyl)-4-[4″-(N-methyl-N-propylaminomethyl)phenyl]thiazole 6o 6 2-(3′-cyanophenyl)-4-[4″-(dimethylaminomethyl)phenyl]thiazole 6u 62-(6″-chloropyrid-3″-yl)-4-[4′-(N- allyl-N-methyl-aminomethyl)phenyl]thiazole 8c 8 5-(4′-methoxyphenyl)-3-[4″-(N-methyl-N-allylaminomethyl)phenyl]-1,2,4- thiadiazole 6p 62-(4′-methyl-3′-nitrophenyl)-4-[4″-(N- methyl-N-propylaminomethyl)-phenyl]thiazole 1jj 1 2-(4′-chlorophenyl)-4-[4″-(N-(2-dimethylaminoethyl)aminomethyl)phenyl] thiazole 5d 52-(3′-nitrophenyl)-4- [amidinothiomethyl)phenyl]thiazole 5e 52-(4′-chlorophenyl)-4-{4-[α-((2- dimethylaminoethyl) amino)acetyl-aminomethyl]phenyl}thiazole 1kk 1 2-(4′-methoxy-3′-nitrophenyl)-4-[4″-(N-methyl-N-allylamino- methyl)phenyl]thiazole 9b 92-(3′-nitrophenyl)-5-[4″-(N-methyl-N- allylaminomethyl)phenyl]-1,3,4-oxadiazole 9d 9 2-(3′nitrophenyl)-5-[4″-(N-methyl-N-allylaminomethyl)phenyl]-1,3,4- thiadiazole 1ll 12-(4′-methoxy-3′-nitrophenyl)-4-[4″- (N-methyl-N-(2-hydroxy-ethyl)amino-methyl)phenyl]thiazole 6q 6 2-(2′-fluoro-4′-trifluoromethylphenyl)-4-[4″-(di- methyl-aminomethyl)phenyl]thiazole 8d8 5-(4′-methoxyphenyl)-3-[4″- (dimethylaminomethyl)phenyl]-1,2,4-thiadiazole 8e 8 5-(4′-methoxyphenyl)-3-[4″-((2-dimethylaminoethyl)thiomethyl)phenyl]- 1,2,4-thiadiazole 5f 52-(4′-bromophenyl)-4-[4″- aminomethylphenyl]thiazole 1mm 12-(4′-methoxy-3′-nitrophenyl)-4-[4″- (N-methyl-N-(2-methylaminoethyl)amino- methyl)phenyl]thiazole 9f 92-(4′-chlorophenyl)-5-[4″- (dimethylaminomethyl)phenyl]-1,3,4-oxadiazole 9g 9 2-(4′-chlorophenyl)-5-[4″-(dimethylaminomethyl)phenyl]-1,3,4- thiadiazole 9h 92-(4′-chlorophenyl)-5-[4″-(N-methyl-N- allylaminomethyl)phenyl]-1,3,4-thiadiazole 9i 9 2-(4′-chlorophenyl)-5-[4″-(N-methyl-N-allylaminomethyl)phenyl]-1,3,4- oxadiazole 1nn 12-(3′nitro-4′-methoxyphenyl)-4-[4″[(2-diethylaminoethylthio)methyl]phenyl]th i-azole 1oo 12-(3′,4′-dimethoxyphenyl)-4-[4″- (dimethylaminomethyl)phenyl]thiazole 9j9 2-(4′-methoxyphenyl)-5-[4″- (dimethylaminomethyl)phenyl]-1,3,4-oxadiazole 9k 9 2-(4′-methoxyphenyl)-5-[4″-(N-methyl-N-allylaminomethyl)phenyl]-1,3,4- oxadiazole 1pp 12-(3′-nitrophenyl)-4-[4″-[(2- dimethylaminoethyl-thio)methyl]phenyl]thiazole 6t 6 2-(4′-fluorophenyl)-4-[3″-acetamido-4″-(dimethylaminomethyl)phenyl]- thiazole 1qq 12-(4′-chlorophenyl)-4-[4″-[(4- methylpiperazin-1-yl)methyl]phenyl]thiazole 1rr 1 2-(4′-chlorophenyl)-4-[4″-[(2-dimethylaminoethyl- thio)methyl]phenyl]thiazole 7b 72-(3′-nitrophenyl)-4-[3″-hydroxyl-4″- (N-methylpiperazino)methylphenyl]-thiazole 3a 3 2-(4′-fluorophenyl)-4-[4″-(2-dimethylaminoethyl)phenyl]thiazole 3b 3 2-(3′-nitrophenyl)-4-[4″-(2-dimethylaminoethyl)phenyl]thiazole 3d 32-(4′-methoxyphenyl)-4-[4″-[2-(N- allyl-N-methylamino)ethyl]phenyl]-thiazole 3e 3 2-(4′-methoxyphenyl)-4-[4″-[2-(N-methylpiperazino)ethyl]phenyl]thiazole 91 9 2-(3′-nitrophenyl)-5-[4″-(thiomorpholinomethyl)phenyl]-1,3,4- thiadiazole 4a 42-(4′-fluorophenyl)-4-[4″-(3- dimethylaminopropynyl)phenyl]thiazole 4b 42-(4′-methoxyphenyl)-4-[4″-(3- dimethylaminopropynyl)phenyl]thiazole 4d4 2-(4′-methoxyphenyl)-4-[4″-(3- dimethylaminopropyl)phenyl]thiazole

244. Organisms

245. Three strains of Candida (Candida parpsilosis, Candida tropicalis,Candida albicans-ATCC 36082) as well as Cryptococcus neoformans wereused for the initial testing. Active compounds were then tested againstfluconazole resistant Candida albicans, Candida krusei, Torulopsisglabrata, and Cryptococcus neoformans along with Sporothrix shenkii andAspergillus flavus in the secondary round of testing. All clinicalstrains used in this study were blood culture isolates from the ClinicalMicrobiology Laboratory of Harbor-UCLA Medical Center, Torrance, Calif.The organisms were maintained on Sabourahd Dextrose Agar slants at 4° C.For experimentation, singlet suspensions of each organism were preparedby growing the yeast overnight at 27° C. on a rotating drum inyeast-nitrogen base broth (YNB) with amino acids (Difco, Detroit,Mich.), pH 7.0 with 0.05M morpholinepropanesulfonic acid (MOPS). Thesuspension was then centrifuged and washed twice with 0.85% NaCl. Thiswas followed by sonication of the washed cell suspension for 4s (BransonSonifier, model 350, Danbury, Conn.). The singlet blastospores werecounted in a hemocytometer and adjusted to the desired concentration in0.85% NaCl.

246. Antifungal Activity

247. The antifungal activity of the compounds and Fluconazole againstthe Candida and Cryptococcus strains were determined using amodification of a broth microdilution technique. Test compounds werediluted in DMSO to a 1.0 mg/ml ratio then diluted to 64 μg/ml in YNBbroth, pH 7.0 with MOPS (Fluconazole was used as the control). This wasto provide a working solution of each compound. Using a 96-well plate,wells 1 and 3 through 12 were prepared with YNB broth, ten folddilutions of the compound solution were made in wells 2 through 11(concentration ranges were 64 to 0.125 μg/ml) Well one served as asterility control and blank for the spectrophotometric assays. Welltwelve served as a growth control. The microtiter plates were inoculatedwith 10 ul in each of well 2 through 11 (final inoculum size was 10⁴organisms/ml). Inoculated plates were incubated for 48 hrs., at 35° C.The MIC values were determined spectrophotometrically by measuring theabsorbance at 420 nm (Automatic Microplate Reader, DuPont Instruments,Wilmington, Del.) after agitation of the plates for 2 min with avortex-mixer (Vorte-Genie 2 Mixer, Scientific Industries, Inc., Bolemia,N.Y.). The MIC endpoint was defined as the lowest drug concentrationexhibiting approximately 50% (or more) reduction of the growth comparedwith the control well. With the turbidity assay this was defined as thelowest drug concentration at which turbidity in the well was <50% of thecontrol (IC₅₀) Minimal Cytolytic Concentrations (MCC) were determined bysubculturing all wells from the 96-well plate onto a Sabourahd DextroseAgar (SDA) plate and incubated for 1 to 2 days at 35° C. and theviability was checked.

248. The following Table II demonstrates the antifungal activities of aselected number of examples. TABLE II C. Crypto. Example # MIC^(a)MCC^(b) MIC MCC MIC MCC MIC MCC 1h 0.5^(c) 2 0.25 1 0.125 0.5 0.5 2 1k0.5 1 0.25 0.5 0.25 0.25 0.25 0.5 1o 1   4 1 4 2 32 0.125 2 1x 1   2 1 21 2 2 2 5b 1   4 1 4 1 4 1 4 6k 1   2 0.5 2 1 2 1 1 6l 0.5 1 0.25 0.50.25 1 0.25 0.5 1gg 1   2 1 4 1 2 1 2 6p 1   8 1 4 2 16 1 4 1kk 1   20.25 1 1 2 0.5 2 9c 1   4 1 1 1 1 2 4 7a 1   4 1 0.25 1 2 1 4 1 4^(c) 164 16 4 16 4 16 1g 2   8 4 8 2 8 2 8 1n 8   16 4 8 8 16 8 8 2b 4   16 216 4 16 4 16 6e 4   4 2 4 2 16 0.5 1 1u 8   8 4 4 4 4 4 4 6f 8   16 4 82 8 4 8 1aa 4   4 4 4 4 4 4 4 1ee 4   16 2 16 4 8 2 16 6m 4   8 4 4 4 84 4 1tt 4   16 4 16 2 16 2 4 6o 2   4 2 8 2 >64 8 16 1jj 8   8 4 4 4 4 88 1ll 8   8 2 2 4 4 2 8 6g 8   4 4 2 8 4 4 4 9j 4   32 8 8 0.5 0.5 0.258 1gg 4   8 4 8 4 8 4 8 1rr 4   8 4 8 4 8 4 8 Fluconazole  0.25 >640.5 >64 0.25 >64 1.0 >64 0.5 >64 1.0 >64 1.0 >64 0.5 >64 Amp-B  0.250.25 <0.03 Naftifine 32   4.0

What is claimed is:
 1. A compound of the formula:

wherein: Ar is phenyl, thienyl or pyridyl substituted by R¹ and R²;where R¹, R² are the same or different and represent hydrogen, halo,alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylthio, amino,hydroxy, cyano, nitro, carboxy, aminocarbonyl or aminosulfonyl,alkylamino, dialkylamino, acylamino, dialkylaminosulfonyl oralkylaminosulfonyl or taken together R¹ and R² may be combined to form—O—(CH₂)_(n)—O— where n is an integer having a value of 1 or 2; R³ andR⁴ are the same or different and represent hydrogen, alkyl which may beoptionally substituted by amino, alkylamino, dialkylamino, hydroxy,cyano, carboxy alkenyl, alkynyl or acyl, taken together R³ and R⁴ may becombined to form —(CH₂)m—Q—(CH₂)m′— where Q is selected from among CH₂,O, S(O)_(n) or NR⁷ where n is an integer having a value of 0, 1, or 2;R⁷ is lower alkyl and m and m′ are integers having a value of 2 with theproviso that when Q is CH₂, m′ may also have a value of 1; R⁵ is H,halo, OR, OH, NO₂, NH₂ and NHCOR where R is alkyl, lower alkyl or aryl;X is N, O or S. Y is N or S; with the proviso when X is O or S, Y mustbe N; Z is N, CR⁸, where R⁸ is hydrogen, halo, lower alkyl oralkoxycarbonyl; with the proviso that X, Y, Z cannot all represent N atthe same time; VR³R⁴ represents heterocyclic rings selected from amongpyrrole, immidazole, 1,3,4-triazole,1,2,4-triazole and pyrazole linkedvia the nitrogen; V is N, O, or S; and P is 1-3; and the non-toxicpharmacologically acceptable salts thereof.
 2. A compound according toclaim 1 of the formula;

wherein: R¹, R², R³, R⁴ R⁵′ p -and V are each as defined in claim 1 andR⁶ is hydrogen, halogen, carboxy, alkoxycarbonyi, lower alkyl, hydroxyand lower alkoxy; and the nontoxic pharmaceutically acceptable saltsthereof.
 3. A compound according to claim 1 of the formula:

wherein: R¹, R², R³, R⁴, R⁵, p and V are as defined in claim 1 and thenontoxic pharmaceutically acceptable salts thereof.
 4. A compoundaccording to claim 1 of the formula:

wherein: R¹, R², R³, R⁴, R⁵, p and V are as defined in claim 1 and thenontoxic pharmaceutically acceptable salts thereof.
 5. A compoundaccording to claim 1 of the formula:

wherein: R¹, R², R³, R⁴, R⁵, p and V are as defined in claim 1 and thenontoxic pharmaceutically acceptable salts thereof.
 6. A compoundaccording to claim 2 of the formula:

wherein: R¹, R², R³, R⁴ are as defined in claim 1 ; and the nontoxicpharmaceutically acceptable salts thereof.
 7. A compound according toclaim 4 of the formula:

wherein: R¹, R², R³, R⁴ are as defined in claim 1 and X is O or S; andthe nontoxic pharmaceutically acceptable salts thereof.
 8. A compoundaccording to claim 5 of the formula:

wherein: R¹, R² R³, R⁴ are as defined in claim 1 ; and the nontoxicpharmaceutically acceptable salts thereof.
 9. An azole according toclaim 1 selected from the group consisting of

wherein: A_(R) is selected from among pyridyl, halo substituted pyridyland

where R⁸ is hydrogen, halo, nitro, amino, triflouromethoxy, pyrrolyl,lower alkoxy, trifluoromethyl, cyano, lower alkynyl and trimethylsilyllower alkynyl; and R⁹ is hydrogen, nitro, lower alkoxy or cyano; X is Sor O; Y is CH or N; Z is CH or N; B is lower alkylene or loweralkynylene; D is SR¹⁰, OR¹¹ or N(R¹²R¹³) wherein R¹⁰ is di-loweralkylaminalkyl; R¹¹ is lower alkenyl, lower alkynyl or lower alkoxyakyl;R¹² and R¹³ are the same or different and represent hydrogen, loweralkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lowercycloalkyl, lower dialkylaminoalkyl, hydroxy-lower alkyl, loweralkylaminoalkyl, mononuclear lower alkyl, di-loweralkylaminoalkylcarbonyl or, taken together, R¹² and R¹³ may be combinedto form —CH₂CH₂N(R¹⁴)CH₂CH₂— or —CH₂CH₂SCH₂CH₂— where R¹⁴ representslower alkyl; and R¹⁵ is hydrogen, nitro, amino, lower alkanamido orhydroxy; and the nontoxic pharmacologically acceptable salts thereof.10. An azole according to claim 9 of the formula:

wherein: R⁸ is hydrogen, halo, nitro, amino, triflouromethoxy, pyrrolyl,lower alkoxy, trifluoromethyl, cyano, lower alkynyl, trimethylsilyllower alkynyl; and R⁹ is hydrogen, nitro, lower alkoxy or cyano; R¹² andR¹³ are the same or different and represent hydrogen, lower alkyl, loweralkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lower cycloalkyl,lower dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl,mononuclear lower alkyl, di-lower alkylaminoalkylcarbonyl or, takentogether, R¹² and R¹³ may be combined to form —CH₂CH₂N(R¹⁴)CH₂CH₂— or—CH₂CH₂SCH₂CH₂— wherein R¹⁴ represents lower alkyl, R¹⁵ is hydrogen,nitro, amino, lower alkanamido or hydroxy; and n is an integer having avalue of 1 to 3, and the nontoxic pharmacologically acceptable saltsthereof.
 11. A thiazole according to claim 10 of the formula:

wherein: R¹⁶ is hydrogen, halo, nitro, lower alkoxy, cyano,trifluoromethyl or lower alkyl; R¹⁷ is hydrogen, nitro, halogen orcyano; R¹⁸ and R¹⁹ are the same or different and represent hydrogen,lower alkyl, lower alkenyl, di-lower alkylaminoalkyl, hydroxy loweralkyl and lower alkylaminoalkyl; and R²⁰ is hydrogen or hydroxy, and thenontoxic pharmacologically acceptable salts thereof.
 12. An azoleaccording to claim 9 of the formula:

wherein: X is S or; R²¹ is selected from among hydrogen and loweralkoxy; R²² is selected from among hydrogen and nitro; and R²³ and R²⁴are lower alkyl, and the nontoxic pharmacologically acceptable saltsthereof.
 13. An azole according to claim 9 of the formula

wherein: E is SR²⁶ or NR²⁷R²⁸ wherein R²⁶ is di-lower alkylaminoalkylR²⁷ and R²⁸ are the same or different and represent lower alkyl andlower alkenyl, and the nontoxic pharmacologically acceptable saltsthereof. 14.Allylaminomethyl)phenyl]-thiazole2-(4′-nitrophenyl)-4-[4″-(N-methyl-N-allylaminomethyl)phenyl]-thiazole.15.2-(3′-nitrophenyl)-4-[4″-(N-methyl-N-allylaminomethyl)phenyl]thiazole.16.2-(4′-methoxy-3-nitrophenyl)-4-[4″-(dimethylaminomethyl)phenyl]thiazole.17.2-(4′-methoxy-3-nitrophenyl)-4-[4″-N-methyl-N-allylaminomethyl)phenyl]thiazole.18. A pharmaceutical composition comprising an effective amount of acompound of claim 1 in combination with a pharmaceutically acceptablecarrier.
 19. A method for treating a fungal infection which comprisesadministering to a mammalian host an effective amount of the compound ofclaim 1 in unit dosage form.
 20. A method for preparing the compounds ofclaim 1 using disclosed process schemes.